The past two-plus decades have witnessed an explosion of research into the development of monoclonal antibodies (mAb) for therapies ranging from cancer and autoimmunity to transplantation, thrombosis and drug addiction. At least 35 such mAb have obtained FDA approval, and many more are in various stages of development and evaluation. A recurring issue with mAb therapy is that patients frequently generate immune responses against the mAb, often reducing their effectiveness, sometimes with serious consequences. Due to the proteinaceous nature of the therapy, these reactions to passive mAb therapy are dependent upon CD4 T cells that perceive part of the mAb as foreign. These reactions still occur despite extensive efforts to eliminate foreignness from the mAb heavy and light chain polypeptides. Even fully human mAb, derived from human antibody genes expressed in mice or from phage display libraries of human antibody genes, can be perceived as foreign by human CD4 T cells due to extensive CDR3 diversity and somatic mutations. Eliminating these somatic alterations is risky because they are often necessary for conferring a high binding affinity to the mAb. My laboratory has many years of experience with somatic hypermutation and CD4 T cell cognition and responses to mutated sequences within V regions of soluble immunoglobulin and B cell receptors. We are well-positioned to exploit this experience and recent progress to develop a strategy for generating reagents that can induce tolerance to mAb in the CD4 T cell repertoire, so that unwanted immune reactions to therapeutic mAb can be averted. We will test the feasibility of our tolerance strategy in a well-defined mouse model. Our strategy is simple, can be applied to any mAb, and is expected to present few regulatory hurdles, enabling potential widespread clinical application.